We propose to develop and analyze, using modern large scale computing techniques, models of critical aspects of the immune system with the ultimate goal of understanding immune regulation. It is difficult to comprehend in the absence of mathematical models the operation of a large system of elements that interact according to nonlinear dynamical laws. Because in vivo phenomenon involve interactions among large numbers of immune system components, in vitro experiments fail to provide answers to many crucial questions. We seek to develop a new generation of models with which we can explore : (1) The role of immune complexes in immune regulation. It have been shown in vitro that when immune complexes span Fc-gamma receptors and surface immunoglobulin receptors on B cells, inhibition of B cell proliferation and differentiation can result. Immune complexes also bind follicular dendritic cells, where they may be retained and stimulate B cells for long periods of time. Because immune complexes form and breakup as antigen and antibody concentrations change, complex feedback mechanisms can be induced. Our models will address how such controls work in vivo. (2) When antigen-antibody or idiotypic (id) anti-id complexes are picked up, processed and presented by B cells to T cells, a phenomena known as intramolecular help can occur, whereby B cells can obtain help from non- antigen specific T cells. Models will be developed to explore the implications of this phenomena in immune networks, anti-id vaccine therapy and autoimmune disease. (3) Network models have left out important features, such as T cell help, immune complex regulation, effects of self and foreign antigen, and distinguishing between B-1 and B-2 cells. We propose to examine the influences of such modifications. (4) The B cell repertoire expressed by an adult influences an animal's ability to respond to disease. We will use our models to examine how network interactions can lead to clonal dominance of cells expressing the T15 idiotype in the response to the bacterial polysaccharide phosphorylcholine. Most important is that progress in developing comprehensive models will provide an increased understanding of the operation of the immune system as a whole in fighting disease. Increased understanding of immune regulation can help in the design of new treatments and therapies for autoimmune disease, bacterial infection, allergies and other immune system disorders.